Process for the preparation of vilazodone hydrochloride and its amorphous form

ABSTRACT

The present invention relates to an improved process for the preparation of vilazodone Hydrochloride and a process for preparation of novel pure amorphous form of vilazodone hydrochloride.

RELATED APPLICATION

This application claims the benefit of priority of our Indian patentapplication numbers 1187/MUM/2012 filed on 12 Apr. 2012 and1784/MUM/2012 filed on 21 Jun. 2012 which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to an improved, commercially viable andindustrially advantageous process for the preparation of Vilazodone or apharmaceutically acceptable salt thereof in high yield and purity. Morespecifically the present invention relates to an improved andindustrially advantageous process for the preparation of VilazodoneHydrochloride. The present invention also provides a novel pureamorphous form of vilazodone hydrochloride, process for preparation,pharmaceutical compositions, and method of treating thereof.

BACKGROUND OF THE INVENTION

Vilazodone is5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamideand represented by formula (I).

The product is marketed in the form of Hydrochloride salt. The currentpharmaceutical product containing this drug is being sold by Merck usingthe trade name Viibryd. Vilazodone is an SSRI antidepressant developedby Clinical Data for the treatment of major depressive disorder.

Vilazodone was first described in U.S. Pat. No. 5,532,241. Example 4 ofSaid patent described process for preparing vilazodone by reacting1-[4-{5-cyanoindol-3-yl)butyl]-4-{2-carboxybenzofuran-5-yl)-piperazineat first with 2-chloro-1-methylpyridinium methanesulfonate inN-methylpyrrolidine and then with dried ammonia. Customary working upgives the free base vilazodone. Which is further converted in toVilazodone hydrochloride.

Journal of Medicinal Chemistry (2004), 47(19), 4684-4692 discloseprocess for preparation of vilazodone as per below scheme.

Org. Process Res. Dev., 2012, 16 (9), pp 1552-1557 discloses process asper below scheme.

The main problem associated with these processes is that it involves useof less economical reagent such as 2-chloro-1-methylpyridinium methanesulphonate and solvent such as N-methyl pyrrolidine.

Zhongguo Yaowu Huaxue Zazhi (2012), 22(1), 74-75, 81 discloses manypossible ways for synthesis of vilazodone.

None of the prior art disclosing direct conversion of ester to amide.All prior art references shows first conversion of ester of compound offormula II in to corresponding acid and then reaction of acid withammonia in presence of solvent and catalyst to prepare vilazodone.

Org. Process Res. Dev., 2012, 16 (9), pp 1552-1557 article disclose thatno vilazodone was obtained during direct conversion of ester to amide.

The above processes for preparation of Vilazodone require many numbersof steps and involve unfriendly reagents. The process is lesseconomical, relatively less safe and time-consuming. Hence suchtechnology is not readily suitable for commercial production. Therefore,the present invention provides a process in which directly esterconverts in to amide.

PCTpublication no. W02002102794A2 describes different polymorphs ofVilazodone hydrochloride, termed as form I to form XVI. W02002102794A2describes form XVI as amorphous form. The term “amorphous” means a solidwithout long-range crystalline order. However, the X-ray powderdiffraction pattern of form XVI shows that the polymorph is not in itspure amorphous form but also comprises crystalline peaks. Therefore, itdoes not demonstrate the amorphous nature of the product. It isessentially a mixture of crystalline and amorphous form which is not aform of suitable choice.

Polymorphic purity is one of the important aspects in the development ofany active pharmaceutical ingredients. An active pharmaceuticalingredient is always preferred to have consistency in terms ofpolymorphic purity. Therefore it is desirable to have either purecrystalline form or a substantially pure amorphous form.

Solvent medium and mode of isolation play very important role inobtaining a polymorphic form over the other.

Accordingly, there remains a need in the art for a novel, stable andsubstantially pure amorphous form of Vilazodone hydrochloride. Thepresent inventors have directed its research work to get the desiredpolymorphic purity.

Based on the aforementioned drawbacks, prior art processes found to beunsuitable for preparation of vilazodone at lab scale and commercialscale operations. Hence, a need still remains for an improved andcommercially viable process of preparing pure vilazodone or apharmaceutically acceptable salt thereof that will solve the aforesaidproblems associated with process described in the prior art and will besuitable for large-scale preparation, in lesser reaction time, in termsof simplicity, purity and yield of the product.

SUMMARY OF THE INVENTION

The present inventors have focused on the problems associated with theprior art processes and have developed an improved process for thepreparation of vilazodone.

As a whole, a process such as the one provided by the present inventionhas the advantage of high yields is achieved with very simple steps.Likewise, said process is not toxic and allows starting from inexpensiveand non-hazardous reactants, providing vilazodone, with a good yield andpharmaceutical quality. All of this contributes in reducing the overallcost of the process, making it commercially interesting and allowing itto be put into practice on an industrial level.

Therefore, in one aspect the present invention provides a process forpreparing vilazodone or a salt thereof, comprising a step of obtaining acompound of formula I or a salt there of, from compound of formula II.

Therefore, in another aspect the present invention provides a processfor preparation of vilazodone a compound of formula (I) or a saltthereof, comprising a step of reacting compound of formula II withsource of ammonia to get a compound of formula (I).

Therefore, in another aspect the present invention provides a processfor preparation of vilazodone or a salt thereof, comprising a step ofobtaining a compound of formula I or a salt there of, from compound offormula II in presence of source of ammonia and any suitable solvent.

Source of ammonia is selected from ammonia gas, liquid ammonia, aqueousammonia, ammonium hydroxide, magnesium nitride and formamide with base;more preferably ammonia gas. Suitable solvent is selected from water,alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons,polar aprotic solvents, polar solvents, chloro solvents, nitriles ormixtures thereof. polar aprotic solvents such as acetone, DMF,acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol,propanol, butanol, glycerol, propylene glycol; polyglycols such aspolyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone; glycolethers such as propylene glycol monomethyl ether, dipropylene glycolmonomethyl ether and diethylene glycol ethyl ether, N,N,-dimethylacetamide, PEG 300, propylene glycol; chloro solvents like methylenechloride, chloroform and ethylene chloride; hydrocarbon solvents liketoluene, xylene, heptane, cyclohexane and hexane; more preferably DMSO.

Therefore, in another aspect the present invention provides a processfor preparation of vilazodone or a salt thereof, comprising a step ofobtaining a compound of formula I or a salt there of, from compound offormula II in presence suitable solvent under ammonia gas pressure.

Therefore, in another aspect the present invention provides a novelcompound ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylatedihydrochloride.

Therefore, in another aspect the present invention provides a novelcompound ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylate hydrobromide.

Therefore, in another aspect the present invention provides a processfor preparation of ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylatedihydrochloride comprises reaction of compound of formula (VI) withBis(2-chloroethyl) amine hydrochloride in presence of suitable base,suitable solvent and phase transfer catalyst.

Phase transfer catalyst is selected from the group consisting ofquaternary ammonium cations, quaternary phosphonium cations, and cyclicpolyethers such as tricaprylylmethylammonium chloride, methyl tributylammonium chloride, methyl tributyl ammonium fluoride, tetrabutylammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammoniumhydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide, tetrabutyl phosphonium chloride,tetraoctylphosphonium bromide, and mixtures thereof. Suitable solvent isselected from water, alcohols, ketones, diols, triols, esters, amides,ethers, hydrocarbons, polar aprotic solvents, polar solvents, chlorosolvents, nitriles or mixtures thereof. Polar aprotic solvents such asacetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol,ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols suchas polyethylene glycol 200, polyethylene glycol 300 and polyethyleneglycol 400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone;glycol ethers such as propylene glycol monomethyl ether, dipropyleneglycol monomethyl ether and diethylene glycol ethyl ether, N,N,-dimethylacetamide, PEG 300, propylene glycol; chloro solvents like methylenechloride, chloroform and ethylene chloride; hydrocarbon solvents liketoluene, xylene, heptane, cyclohexane and hexane, more preferably DMSO.Suitable base is selected from the group of alkali or alkaline earthmetal hydroxide, carbonate, bicarbonate.

Therefore, in another aspect the present invention provides a processfor preparation of vilazodone or a salt thereof, comprising purificationof vilazodone base with any suitable solvent and suitable baseoptionally in presence of water, wherein suitable solvent is selectedfrom group of polar aprotic solvents such as acetone, DMF, acetonitrile,DMSO, sulfolane, DMAC, NMP etc. Suitable base is selected from the groupof alkali or alkaline earth metal hydroxide, carbonate, bicarbonate.wherein the suitable base is selected from NaOH, KOH, LiOH, NaHCO₃,KHCO₃, LiHCO₃, Na₂CO₃, K₂CO₃, Li₂CO₃, Mg(OH)₂, Ca(OH)₂, CaCO₃, MgCO₃,Ba(OH)₂, Be(OH)₂, BaCO₃, SrCO₃ and the like or mixtures thereof.

Therefore, in another aspect the present invention provides a processfor preparation of vilazodone or a salt thereof, comprising purificationof vilazodone base by treatment of vilazodone base with DMF and aqueoussodium hydroxide solution.

Therefore, in another aspect the present invention provides a novelcompound process for preparation of vilazodone or a salt thereof,comprising crystallizing vilazodone base from DMSO and water.

Therefore, in another aspect the present invention provides a processhaving a content of5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxylicacid is less than 1% by mole; more preferably less than 0.5% by mole;more specifically less than 0.15% by mole.

Therefore, in another aspect the present invention provides a novelcompound novel crystalline form A of Vilazodone.

Therefore, in another aspect the present invention provides a novelcompound Crystalline form A of Vilazodone, having an X-ray diffractionpattern comprising at least five peaks selected from 2theta values 5.8,13.9, 18.6, 20.9, 21.9±0.3.

Therefore, in another aspect the present invention provides a processfor preparing crystalline form A of vilazodone base, comprising thesteps of: (a) dissolving vilazodone base in one or more organicsolvent(s), (b) causing crystalline form A to precipitate from thesolution obtained in step (a), and (c) isolating the crystalline form Aobtained in step (b).

Therefore, in another aspect the present invention provides a novelcompound amorphous vilazodone base.

Therefore, in another aspect the present invention provides a processfor preparing amorphous vilazodone base, comprising the steps of: (a)dissolving vilazodone base in one or more organic solvent(s), (b)causing an amorphous solid to precipitate from the solution obtained instep (a), and (c) isolating the amorphous solid obtained in step (b).

Therefore, in another aspect the present invention provides a novelcrystalline form II of ethyl5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylatehydrochloride.

Therefore, in another aspect the present invention provides a novelcompound Crystalline form II of ethyl5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylatehydrochloride, having an X-ray diffraction pattern comprising at leastfive peaks selected from 2theta values 11.7, 18.86, 22.75, 23.3,24.7±0.3.

Therefore, in another aspect the present invention provides a processfor preparation of vilazodone comprises condensation of compound offormula (VII) or salt thereof with compound of formula (VIII) to getcompound of formula (II) or salt thereof in presence of triethyl amineand tetrabutyl ammonium bromide.

Therefore, in another aspect the present invention provides a processfor preparation of vilazodone comprises condensation of compound offormula (VII) hydro bromide salt with compound of formula (VIII) to getcompound of formula (II).

Therefore, in another aspect the present invention provides a processfor the preparation of vilazodone or a salt thereof which comprises,

-   -   a. reacting 5-nitro salicaldehyde of formula (III) with 2-bromo        diethyl malonate of formula (IV) to get compound of formula (V),

-   -   b. reducing compound of formula (V) to get compound of formula        (VI)

-   -   c. converting compound of formula (VI) to compound of formula        (VII),

-   -   d. Condensing compound of formula (VII) or salt thereof with        compound of formula (VIII) to get compound of formula (II) or        salt thereof,

-   -   e. reacting compound of formula (II) with source of ammonia to        get compound of formula (I)

The present inventors have now surprisingly and unexpectedly discovereda novel pure amorphous form of Vilazodone hydrochloride with highpurity, adequate stability and good dissolution properties.

In one aspect, the present invention provides a novel, pure and stableamorphous form of Vilazodone hydrochloride.

In one aspect, the present invention provides a novel, pure and stableamorphous form of Vilazodone hydrochloride characterized by X-raydiffraction pattern as depicted in Figure-1.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising amorphous Vilazodone hydrochloride of the presentinvention and one or more pharmaceutically acceptable excipients.

In another aspect, the amorphous Vilazodone hydrochloride disclosedherein for use in the pharmaceutical compositions of the presentinvention, wherein 90 volume-percent of the particles (D90) have a sizeof less than or equal to about 500 microns, specifically less than orequal to about 300 microns, more specifically less than or equal toabout 200 microns, still more specifically less than or equal to about100 microns, and most specifically less than or equal to about 15microns.

In another aspect, the present invention further encompasses a processfor preparing the highly pure and stable amorphous form of Vilazodonehydrochloride.

In another aspect present invention provides a process for preparationof a stable and substantially pure amorphous form of Vilazodonehydrochloride, which comprises:

a) Providing a solution of Vilazodone hydrochloride in a suitablesolvent or a mixture of solvents capable of dissolving Vilazodonehydrochloride;b) Optionally, filtering the solvent solution to remove any extraneousmatter; andc) Substantially removing the solvent from the solution to affordamorphous form of Vilazodone hydrochloride.

In another aspect of the present invention, suitable solvent in step (a)is selected from the group of formic acid, acetic acid and propionicacid, more preferably formic acid.

In another aspect present invention provides a process for preparationof a stable and substantially pure amorphous form of Vilazodonehydrochloride, which comprises:

a) Providing a solution of Vilazodone hydrochloride in formic acid;b) Optionally, filtering the solvent solution to remove any extraneousmatter; andc) Substantially removing the solvent from the solution to affordamorphous form of Vilazodone hydrochloride.

In another aspect present invention provides a process for preparationof a stable and substantially pure amorphous form of Vilazodonehydrochloride, which comprises:

a) Providing a solution of Vilazodone free base in a suitable solvent ora mixture of solvents capable of dissolving Vilazodone;b) Mixing with the solution of hydrochloric acid dissolved in thesuitable solvent;c) Optionally, filtering the solvent solution to remove any extraneousmatter; andd) Substantially removing the solvent from the solution to affordamorphous form of Vilazodone hydrochloride.

In another aspect of the present invention, suitable solvent in step (a)is selected from the group of formic acid, acetic acid and propionicacid, more preferably formic acid and suitable solvent in step (b) isselected from group comprising water, alcohols, ketones, chlorinatedhydrocarbons, hydrocarbons, nitriles, esters, cyclic ethers, aliphaticethers, polar aprotic solvents, and mixtures thereof. Preferablesolvents are chlorinated hydrocarbons, ketones, alcohols and mixturesthereof, more preferably 2-propanol.

In another aspect present invention provides a process for preparationof a stable and substantially pure amorphous form of Vilazodonehydrochloride, which comprises:

a) Providing a solution of Vilazodone free base in formic acid;b) Mixing with the solution of 2-propanol.HCl;c) Optionally, filtering the solvent solution to remove any extraneousmatter; andd) Substantially removing the solvent from the solution to affordamorphous form of Vilazodone hydrochloride.

In another aspect, the present invention provides a method of treating adepressive disorder, the method comprising:

administering to a patient in need thereof an effective amount of acompound which is a amorphous hydrochloride salt of1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine,wherein a depressive disorder is treated in the patient.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows an X-ray diffraction pattern of novel form II of ethyl5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylate hydrochloride prepared byinventors.

FIG. 2 shows an X-ray diffraction pattern of novel form A of vilazodoneprepared by inventors.

FIG. 3 shows an X-ray diffraction pattern of novel pure amorphous formof vilazodone hydrochloride prepared by inventors.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing vilazodone or asalt thereof, comprising a step of obtaining a compound of formula I ora salt there of, from compound of formula II.

Therefore, in one embodiment the present invention provides a processfor preparation of vilazodone a compound of formula (I) or a saltthereof, comprising a step of reacting compound of formula II withsource of ammonia to get a compound of formula (I).

Therefore, in another embodiment the present invention provides aprocess for preparation of vilazodone or a salt thereof, comprising astep of obtaining a compound of formula I or a salt there of, fromcompound of formula II in presence of source of ammonia and any suitablesolvent.

Source of ammonia is selected from ammonia gas, liquid ammonia, aqueousammonia, ammonium hydroxide, magnesium nitride and formamide with base;more preferably ammonia gas. Suitable solvent is selected from water,alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons,polar aprotic solvents, polar solvents, chloro solvents, nitriles ormixtures thereof polar aprotic solvents such as acetone, DMF,acetonitrile, DMSO, sulfolane; alcohols such as methanol, ethanol,propanol, butanol, glycerol, propylene glycol; polyglycols such aspolyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone; glycolethers such as propylene glycol monomethyl ether, dipropylene glycolmonomethyl ether and diethylene glycol ethyl ether, N,N,-dimethylacetamide, PEG 300, propylene glycol; chloro solvents like methylenechloride, chloroform and ethylene chloride; hydrocarbon solvents liketoluene, xylene, heptane, cyclohexane and hexane; more preferably DMSO.

Therefore, in another embodiment the present invention provides aprocess for preparation of vilazodone or a salt thereof, comprising astep of obtaining a compound of formula I or a salt there of, fromcompound of formula II in presence suitable solvent under ammonia gaspressure.

Therefore, in another embodiment the present invention provides a novelcompound ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylatedihydrochloride.

Therefore, in another embodiment the present invention provides a novelcompound ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylate hydrobromide.

Therefore, in another embodiment the present invention provides aprocess for preparation of ethyl5-(1-piperazinyl)-benzofuran-2-carboxylate dihydrochloride comprisesreaction of compound of formula (VI) with Bis(2-chloroethyl) aminehydrochloride in presence of suitable base, suitable solvent and phasetransfer catalyst.

Phase transfer catalyst is one selected from the group consisting ofquaternary ammonium cations, quaternary phosphonium cations, and cyclicpolyethers such as tricaprylylmethylammonium chloride, methyl tributylammonium chloride, methyl tributyl ammonium fluoride, tetrabutylammonium bromide, tetrabutyl ammonium fluoride, tetrabutyl ammoniumhydrogen sulfate, triethyl benzyl ammonium chloride, tetrabutylphosphonium bromide, tetrabutyl phosphonium chloride,tetraoctylphosphonium bromide, and mixtures thereof. Suitable solvent isselected from water, alcohols, ketones, diols, triols, esters, amides,ethers, hydrocarbons, polar aprotic solvents, polar solvents, chlorosolvents, nitriles or mixtures thereof. Polar aprotic solvents such asacetone, DMF, acetonitrile, DMSO, sulfolane; alcohols such as methanol,ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols suchas polyethylene glycol 200, polyethylene glycol 300 and polyethyleneglycol 400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone;glycol ethers such as propylene glycol monomethyl ether, dipropyleneglycol monomethyl ether and diethylene glycol ethyl ether, N,N,-dimethylacetamide, PEG 300, propylene glycol; chloro solvents like methylenechloride, chloroform and ethylene chloride; hydrocarbon solvents liketoluene, xylene, heptane, cyclohexane and hexane, more preferably DMSO.Suitable base is selected from the group of alkali or alkaline earthmetal hydroxide, carbonate, bicarbonate.

Therefore, in another embodiment the present invention provides aprocess for preparation of vilazodone or a salt thereof, comprisingpurification of vilazodone base with any suitable solvent and suitablebase optionally in presence of water, wherein suitable solvent isselected from group of polar aprotic solvents such as acetone, DMF,acetonitrile, DMSO, sulfolane, DMAC, NMP etc. Suitable base is selectedfrom the group of alkali or alkaline earth metal hydroxide, carbonate,bicarbonate. wherein the suitable base is selected from NaOH, KOH, LiOH,NaHCO₃, KHCO₃, LiHCO₃, Na₂CO₃, K₂CO₃, Li₂CO₃, Mg(OH)₂, Ca(OH)₂, CaCO₃,MgCO₃, Ba(OH)₂, Be(OH)₂, BaCO₃, SrCO₃ and the like or mixtures thereof.

Therefore, in another embodiment the present invention provides aprocess for preparation of vilazodone or a salt thereof, comprisingpurification of vilazodone base by treatment of vilazodone base with DMFand aqueous sodium hydroxide solution.

Therefore, in another embodiment the present invention provides a novelcompound process for preparation of vilazodone or a salt thereof,comprising crystallizing vilazodone base from DMSO and water.

Therefore, in another embodiment the present invention provides aprocess having a content of5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxylicacid is less than 1% by mole; more preferably less than 0.5% by mole;more specifically less than 0.15% by mole.

Therefore, in another embodiment the present invention provides a novelcompound novel crystalline form A of Vilazodone.

Therefore, in another embodiment the present invention provides a novelcompound Crystalline form A of Vilazodone, having an X-ray diffractionpattern comprising at least five peaks selected from 2theta values 5.8,13.9, 18.6, 20.9, 21.9±0.3.

Therefore, in another embodiment the present invention provides aprocess for preparing crystalline form A of vilazodone base, comprisingthe steps of: (a) dissolving vilazodone base in one or more organicsolvent(s), (b) causing crystalline form A to precipitate from thesolution obtained in step (a), and (c) isolating the crystalline form Aobtained in step (b).

Therefore, in another embodiment the present invention provides a novelcompound amorphous vilazodone base.

Therefore, in another embodiment the present invention provides aprocess for preparing amorphous vilazodone base, comprising the stepsof: (a) dissolving vilazodone base in one or more organic solvent(s),(b) causing an amorphous solid to precipitate from the solution obtainedin step (a), and (c) isolating the amorphous solid obtained in step (b).

Therefore, in another embodiment the present invention provides a novelcrystalline form II of ethyl 5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylate hydrochloride.

Therefore, in another embodiment the present invention provides a novelcompound Crystalline form II of ethyl5-(4-(4-(5-cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxylatehydrochloride, having an X-ray diffraction pattern comprising at leastfive peaks selected from 2theta values 11.7, 18.86, 22.75, 23.3,24.7±0.3.

Therefore, in another embodiment the present invention provides aprocess for preparation of vilazodone comprises condensation of compoundof formula (VII) or salt thereof with compound of formula (VIII) to getcompound of formula (II) or salt thereof in presence of triethyl amineand tetrabutyl ammonium bromide.

Therefore, in another embodiment the present invention provides aprocess for preparation of vilazodone comprises condensation of compoundof formula (VII) hydrobromide salt with compound of formula (VIII) toget compound of formula (II).

Therefore, in another embodiment the present invention provides aprocess for the preparation of vilazodone or a salt thereof whichcomprises,

-   -   a. reacting 5-nitro salicaldehyde of formula (III) with 2-bromo        diethyl malonate of formula (IV) to get compound of formula (V),

-   -   b. reducing compound of formula (V) to get compound of formula        (VI)

-   -   c. converting compound of formula (VI) to compound of formula        (VII),

-   -   d. Condensing compound of formula (VII) or salt thereof with        compound of formula (VIII) to get compound of formula (II) or        salt thereof,

-   -   e. reacting compound of formula (II) with source of ammonia to        get compound of formula (I)

The embodiments of present invention are shown in below given scheme.

Vilazodone is converted into one of its acid-addition salts by treatmentwith an acid. In another embodiment present invention provides a processfor preparation of 3-(4-chlorobutyl)-1H-indole-5-carbonitrile.

In one embodiment present invention provides novel pure amorphous formof vilazodone hydrochloride.

In another embodiment, the present invention further encompasses aprocess for preparing the highly pure and stable amorphous form ofVilazodone hydrochloride.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising amorphous Vilazodone hydrochloride of the presentinvention and one or more pharmaceutically acceptable excipients.

In another embodiment, the amorphous Vilazodone hydrochloride disclosedherein for use in the pharmaceutical compositions of the presentinvention, wherein 90 volume-percent of the particles (D90) have a sizeof less than or equal to about 500 microns, specifically less than orequal to about 300 microns, more specifically less than or equal toabout 200 microns, still more specifically less than or equal to about100 microns, and most specifically less than or equal to about 15microns.

According to one embodiment of the present invention, there is provideda stable and substantially pure amorphous form of Vilazodonehydrochloride. Amorphous form of Vilazodone hydrochloride ischaracterized by the following properties: a powder XRD patternsubstantially in accordance with FIG. 1. The X-ray powder diffractionpattern shows no peaks, thus demonstrating the amorphous nature of theproduct.

According to another embodiment of the present invention, a process isprovided for preparation of a stable and substantially pure amorphousform of Vilazodone hydrochloride, which comprises:

a) Providing a solution of Vilazodone hydrochloride in a suitablesolvent or a mixture of solvents capable of dissolving Vilazodonehydrochloride;b) Optionally, filtering the solvent solution to remove any extraneousmatter; andc) Substantially removing the solvent from the solution to affordamorphous form of Vilazodone hydrochloride.

The process can produce amorphous Vilazodone hydrochloride insubstantially pure form.

The term “substantially pure amorphous form of Vilazodone hydrochloride”refers to the amorphous form of Vilazodone hydrochloride having puritygreater than about 98%, specifically greater than about 99%, morespecifically greater than about 99.5% and still more specificallygreater than about 99.9% (measured by HPLC).

The amorphous Vilazodone hydrochloride obtained by the process disclosedherein is stable, consistently reproducible and has good flowproperties, and which is particularly suitable for bulk preparation andhandling, and so, the amorphous Vilazodone hydrochloride obtained by theprocess disclosed herein is suitable for formulating Vilazodonehydrochloride.

The suitable solvent used in step-(a) is selected from the groupcomprising carboxylic acids, such as formic acid, acetic acid, propionicacid etc.

Step-(a) of providing a solution of Vilazodone hydrochloride includesdissolving Vilazodone hydrochloride in the solvent, or obtaining anexisting solution from a previous processing step. Preferably theVilazodone hydrochloride is dissolved in the solvent at a temperature ofbelow about boiling temperature of the solvent used, more preferably atabout 20° C. to about 110° C., and still more preferably at about 25° C.to about 80° C.

The solution in step-(a) may also be prepared by reacting Vilazodonefree base with Hydrochloric acid to produce a solution containingVilazodone hydrochloride, or optionally subjecting the solution to usualwork up such as washings, extractions etc., and dissolving the resultingVilazodone hydrochloride in a suitable solvent at a temperature of belowabout boiling temperature of the solvent used, more preferably at 20° C.to about 110° C., and still more preferably at about 25° C. to about 80°C.

The solution obtained in step-(a) may optionally be subjected to carbontreatment. The carbon treatment can be carried out by methods known inthe art, for example by stirring the solution with finely powderedcarbon at a temperature of below about 70° C. for at least 15 minutes,preferably at a temperature of about 25° C. to about 70° C. for at least30 minutes; and filtering the resulting mixture through hyflo to obtaina filtrate containing Vilazodone hydrochloride by removing charcoal.Preferably, finely powdered carbon is an active carbon.

The solution obtained in step-(a) or step-(b) is optionally stirred at atemperature of about 30° C. to the reflux temperature of the solventused for at least 20 minutes, and preferably at a temperature of about40° C. to the reflux temperature of the solvent used from about 30minutes to about 4 hours.

Removal of solvent in step-(c) is accomplished by, for example,substantially complete evaporation of the solvent, concentrating thesolution and filtering the solid under inert atmosphere. Alternatively,the solvent may also be removed by evaporation.

Evaporation can be achieved at sub-zero temperatures by thelyophilisation or freeze-drying technique. The solution may also becompletely evaporated in, for example, a pilot plant Rota vapor, aVacuum Paddle Dryer or in a conventional reactor under vacuum aboveabout 720 mm Hg by flash evaporation techniques by using an agitatedthin film dryer (“ATFD”), or evaporated by spray drying.

The distillation process can be performed at atmospheric pressure orreduced pressure. Preferably the solvent is removed at a pressure ofabout 760 mm Hg or less, more preferably at about 400 mm Hg or less,still more preferably at about 80 mm Hg or less, and most preferablyfrom about 30 to about 80 mm Hg.

The substantially pure amorphous Vilazodone hydrochloride obtained bythe above process may be further dried in, for example, Vacuum TrayDryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rotavapor, to further lower residual solvents.

The total purity of the amorphous Vilazodone hydrochloride obtained bythe process disclosed herein is of greater than about 99%, specificallygreater than about 99.5%, and more specifically greater than about 99.9%as measured by HPLC.

According to another aspect of the present invention, a process isprovided for preparation of a stable and substantially pure amorphousform of Vilazodone hydrochloride, which comprises:

a) Providing a solution of Vilazodone free base in a suitable solvent ora mixture of solvents capable of dissolving Vilazodone;b) Mixing with the solution of hydrochloric acid dissolved in thesuitable solvent;c) Optionally, filtering the solvent solution to remove any extraneousmatter; andd) Substantially removing the solvent from the solution to affordamorphous form of Vilazodone hydrochloride.

The suitable solvent used in step-(b) is selected from the groupcomprising water, alcohols, ketones, chlorinated hydrocarbons,hydrocarbons, nitriles, esters, cyclic ethers, aliphatic ethers, polaraprotic solvents, and mixtures thereof. Preferable solvents are alcoholsand, more preferably isopropyl alcohol.

Exemplary alcohol solvents include, but are not limited to, C1 to C8straight or branched chain alcohol solvents such as methanol, ethanol,propanol, butanol, amyl alcohol, hexanol, and mixtures thereof. Specificalcohol solvents are methanol, ethanol, isopropyl alcohol, and mixturesthereof, and most specific alcohol solvent is isopropyl alcohol.

Exemplary ketone solvents include, but are not limited to, acetone,methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketoneand the like, and mixtures thereof. Exemplary nitrile solvents include,but are not limited to, acetonitrile, propionitrile and the like, andmixtures thereof.

Exemplary ester solvents include, but are not limited to, ethyl acetate,isopropyl acetate, and the like and mixtures thereof.

Exemplary chlorinated hydrocarbon solvents include, but are not limitedto, methylene chloride, ethyl dichloride, chloroform, carbontetrachloride, and mixtures thereof. Specific chlorinated hydrocarbonsolvent is methylene chloride.

Exemplary cyclic ether solvents include, but are not limited to,tetrahydrofuran, dioxane, and the like, and mixtures thereof.

Exemplary aliphatic ether solvents include, but are not limited to,diethyl ether, diisopropyl ether, monoglyme, diglyme and the like, andmixtures thereof.

Exemplary hydrocarbon solvents include, but are not limited to,n-pentane, n-hexane, n-heptane and isomers thereof, cyclohexane, tolueneand xylene and the like, and mixtures thereof.

Exemplary polar aprotic solvents include, but are not limited to, N,N-dimethylformaniide, N, N-dimethylacetamide, dimethylsulfoxide, andmixtures thereof.

The present invention further illustrated in detail by the belowexamples which are however not limit to the scope of the invention.

EXAMPLES Example-1 Preparation of ethyl5-nitro-1-benzofuran-2-carboxylate

To a solution of DMF (400 ml), K₂CO₃ powder (124.1 g) and 5-nitrosalicylaldehyde (100 g) was slowly added Diethyl bromomalonate (171.7 g)at 30-40° C. under Nitrogen atmosphere. The reaction mixture was stirredat 85-90° C. under Nitrogen atmosphere for 15 hours. Cool the reactionmix to 80-85° C. Cyclohexane (500 ml) was added to the reaction mix at70-85° C. within 1 hour and then stirred the reaction mix at 80-85° C.for 15-30 minutes. The reaction mixture was cooled to 15-20° C. andprocess water (1000 ml) was added to the reaction mixture at 15-20° C.within 1 hour. The reaction mixture was stirred at 20-30° C. for 1-2hour and then the solid was filtered and washed with process water (100ml×5). Dried at 55-60° C. for 8-10 hours. Yield: 95.2%

Example-2 Preparation of ethyl-5-amino-1-benzofuran-2-carboxylate

To a solution of ethyl-5-nitro-1-benzofuran-2-carboxylate (100 g) inEthyl acetate (800 ml) was added 10% palladium on carbon (4.0 g). Thereaction mixture was stirred under an atmosphere of hydrogen at 33-38°C. with 4-5 kg/cm² hydrogen pressure for 4-6 hrs. After completion ofthe reaction, reaction mixture was filtered through hyflo, washed withethyl acetate. The filtrate was concentrated in vacuo to giveethyl-5-amino-1-benzofuran-2-carboxylate yield: 100%

Example-3 Preparation of ethyl5-(1-piperazinyl)-benzofuran-2-carboxylate dihydrochloride

ethyl-5-amino-1-benzofuran-2-carboxylate obtained in above step wasdissolved in o-Xylene (1500 ml) and then Bis(2-chloroethyl) aminehydrochloride (113.8 g), Potassium carbonate powder (108.6 g) and TBAB(5.0 g) at 20-30° C. was added in the reaction mixture. The reactionmixture was maintained for 32 hrs at 135-140° C. After completion of thereaction solid was filtered and washed it with o-Xylene [100 ml×3], suckit dry. The wet cake was charged in the saturated brine solution understirring and ammonia solution (100 ml) was added in the reaction mixtureat 10-15° C. under stirring. The product was extracted in MDC (1000 ml)and washed subsequently with dilute acetic acid and water. Conc. HCl(100.5 g) was charged in MDC layer and then MDC was removedatmospherically up-to 50° C. Ethanol (700 ml) was charged to the residueand raise the temperature of the suspension to 55-60° C. The reactionmass was cooled for 1-2 hours at 20-30° C. and filtered the solid,washed it with Ethanol [100 ml×3]. Dried at 55-60° C. for 12 hours.Yield: 81.3%

Example-4 Preparation of ethyl5-(1-piperazinyl)-benzofuran-2-carboxylate hydrobromide

ethyl-5-amino-1-benzofuran-2-carboxylate obtained in above step wasdissolved in o-Xylene (1500 ml) and then Bis(2-chloroethyl) aminehydrochloride (113.8 g), Potassium carbonate powder (108.6 g) and TBAB(5.0 g) at 20-30° C. was added in the reaction mixture. The reactionmixture was maintained for 32 hrs at 135-140° C. After completion of thereaction solid was filtered and washed it with o-Xylene [100 ml×3], suckit dry. The wet cake was charged in the saturated brine solution understirring and ammonia solution (100 ml) was added in the reaction mixtureat 10-15° C. under stirring. The product was extracted in MDC (1000 ml)and washed subsequently with dilute acetic acid and water. Aqueous HBrwas charged in MDC layer and then MDC was removed atmospherically up-to50° C. Ethanol (700 ml) was charged to the residue and raise thetemperature of the suspension to 55-60° C. The reaction mass was cooledfor 1-2 hours at 20-30° C. and filtered the solid, washed it withEthanol [100 ml×3]. Dried at 55-60° C. for 12 hours. Yield: 81.3%

Example-5 Preparation of ethyl5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxylatehydrochloride

A mixture of ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylatedihydrochloride (100 g), 3-(4-chlorobutyl)-1H-indole-5-carbonitrile(63.7 g), triethyl amine (400 ml) and TBAB (88.3 g) were heated at85-90° C. (reflux) under stirring for 10 hrs. After completion of thereaction Acetone (400 ml) was charged to the residue and reflux thereaction mass at 55-60° C. under stirring for 30-45 minutes. Thereaction mass was cooled to 45-50° C. and activated carbon (5.0 g) wascharged to reaction mass and again refluxed for 15-30 minutes. Thereaction mass was cooled to 15-20° C. and filtered through hyflo andwashed with acetone. IPA.HCl (˜100 ml) was added to the solution at50-55° C. in more than 30 minutes to adjust the pH 2.0 under stirringand maintained for 45-60 minutes at reflux. The reaction mix was cooledto 20-30° C. under stirring for 2-3 hours and then maintained at 0-5° C.for 45-60 minutes under stirring. The solid was filtered and washed withAcetone. Dried at 55-60° C. for 4-6 hours. Yield: 83%

Example-6 Preparation of ethyl5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxylatehydrochloride

A mixture of ethyl 5-(1-piperazinyl)-benzofuran-2-carboxylatehydrobromide (100 g), 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (63.7g), triethyl amine (400 ml) and TBAB (88.3 g) were heated at 85-90° C.(reflux) under stirring for 10 hrs. After completion of the reactionAcetone (400 ml) was charged to the residue and reflux the reaction massat 55-60° C. under stirring for 30-45 minutes. The reaction mass wascooled to 45-50° C. and activated carbon (5.0 g) was charged to reactionmass and again refluxed for 15-30 minutes. The reaction mass was cooledto 15-20° C. and filtered through hyflo and washed with acetone. IPA.HCl(˜100 ml) was added to the solution at 50-55° C. in more than 30 minutesto adjust the pH 2.0 under stirring and maintained for 45-60 minutes atreflux. The reaction mix was cooled to 20-30° C. under stirring for 2-3hours and then maintained at 0-5° C. for 45-60 minutes under stirring.The solid was filtered and washed with Acetone. Dried at 55-60° C. for4-6 hours. Yield: 83%

Example-7 Preparation of Vilazodone

To a solution of DMSO (400 ml) and Stage-II (100 g) in the Hydrogenatorat 20-30° C. Ammonia gas was charged with 5-6 kg pressure. The reactionmix was maintained to 30-35° C. at 5-6 kg Ammonia pressure for 16-18hours. After completion of the reaction ammonia gas was released thetemperature of reaction mass was raised to 50-55° C. Activated carbon(5.0 g) was charged to the reaction mass at 50-55° C. and maintained at55-60° C. for 15-30 minutes. The reaction mixture was filtered throughhyflo and washed with hot (50-55° C.) DMSO (75 ml). Charged the filtratein hot DM Water (2000 ml) at 80-85° C. within 1 hour. The reaction mixwas maintained at 80-85° C. for 30-45 minutes. The solid was filteredand washed with hot water. Suck dried it. The wet cake (75 g) wascharged with DMF (450 ml) and the temperature of reaction mix was raisedto 50-55° C. Sodium hydroxide solution (dissolve 9.8 g NaOH in 10 ml DMWater) was added to the reaction mass and activated carbon (3.75 g) at50-55° C. The reaction mix was maintained at 50-55° C. for 30-45minutes. The reaction mix was filtered through hyflo and washed with hot(50-55° C.) DMF: DM Water mix [(38.5 ml+19.2 ml)×2]. The reactionmixture was cooled for 2-3 hours at 20-30° C. and filtered the solid.Suck dried it completely. Then again wet cake was dissolved in DMSO (350ml) at 50-55° C. and charged this clear solution in hot water (1500 ml)at 80-85° C. within 1 hour. Maintain the reaction mix was maintained at80-85° C. for 30-45 minutes and the solid was filtered and washed withDM Water (75 ml×3) at 80-85° C. Suck it dried. Dried it at 55-60° C.Yield: 81.6%

Example-8 Preparation of Amorphous Form of Vilazodone Hydrochloride

Formic acid (500 ml) and vilazodone base (100 g) and 20% w/whydrochloric acid were mixed at 20-30° C. under stirring. Activatedcarbon (5.0 g) was added and reaction mass was stirred for 30-45 minutesat 30-35° C. The reaction mass was filtered hot and washed with hot(30-35° C.) Formic acid (100 ml). The spray dryer aspirator was set at1400 rpm (vacuum at 50-120 mm), inlet temperature 125-130° C., and airpressure at 3-4 Kg/cm2 and feed pump rate of 2-3 rpm. Then filtrate wasspray dried. The material was unloaded and dried in VTD at 85-90° C. for20-24 hours. Yield: 83.3%

Example-9 Preparation of Amorphous Form of Vilazodone Hydrochloride

Vilazodone hydrochloride (2.0 g) was dissolved in formic acid (10 ml) toobtain clear solution. The solvents were removed completely under vacuumat 40° C. and then dried for 12 hours to give 2.0 g of Vilazodonehydrochloride in amorphous form.

Example-10 Preparation of Amorphous Form of Vilazodone Hydrochloride

Formic acid (500 ml) and vilazodone base (100 g) and IPA.HCl were mixedat 20-30° C. under stirring. Activated carbon (5.0 g) was added andreaction mass was stirred for 30-45 minutes at 30-35° C. The reactionmass was filtered hot and washed with hot (30-35° C.) Formic acid (100ml). The spray dryer aspirator was set at 1400 rpm (vacuum at 50-120mm), inlet temperature 125-130° C., and air pressure at 3-4 Kg/cm2 andfeed pump rate of 2-3 rpm. Then filtrate was spray dried. The materialwas unloaded and dried in VTD at 85-90° C. for 20-24 hours.

1.-32. (canceled)
 33. A process for preparation of Vilazodone a compoundof formula (I) or a salt thereof, comprising a step of reacting compoundof formula (II) with source of ammonia to get a compound of formula (I).


34. The process according to claim 33, further comprising a step ofadding a suitable solvent.
 35. The process as claimed in claim 33,wherein source of ammonia is selected from the group consisting ofammonia gas, liquid ammonia, aqueous ammonia, ammonium hydroxide,magnesium nitride and formamide with base.
 36. The process as claimed inclaim 34, wherein said suitable solvent is selected from water,alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons,polar aprotic solvents, polyglycols, pyrrolidones, glycol ethers, polarsolvents, chloro solvents, hydrocarbon solvents, nitriles or mixturesthereof; wherein said polar aprotic solvent is selected from the groupconsisting of acetone, DMF, acetonitrile, DMSO, and sulfolane; whereinsaid alcohols is selected from the group consisting of methanol,ethanol, propanol, butanol, glycerol, and propylene glycol; wherein saidpolyglycols is selected from the group consisting of polyethylene glycol200, polyethylene glycol 300, and polyethylene glycol 400; wherein saidpyrrolidones is selected from the group consisting of N-methylpyrrolidone and 2-pyrrolidone; wherein said glycol ethers is selectedfrom the group consisting of propylene glycol monomethyl ether,dipropylene glycol monomethyl ether, diethylene glycol ethyl ether,N,N,-dimethyl acetamide, PEG 300, and propylene glycol; wherein saidchloro solvents is selected from the group consisting of methylenechloride, chloroform, and ethylene chloride; wherein said hydrocarbonsolvents is selected from the group consisting of toluene, xylene,heptane, cyclohexane, hexane, and DMSO.
 37. The process according toclaim 33, further comprising a purification step of Vilazodone base witha suitable solvent and a suitable base optionally in presence of water.38. The process claimed in claim 37, wherein said suitable solvent is anaprotic solvent selected from the group consisting of acetone, DMF,acetonitrile, DMSO, sulfolane, DMAC, and NMP.
 39. The process claimed inclaim 37, wherein said suitable base is selected from the groupconsisting of alkali or alkaline earth metal hydroxide, carbonate, andbicarbonate.
 40. The process claimed in claim 39, wherein said suitablebase is selected from the group consisting of NaOH, aqueous sodiumhydroxide, KOH, LiOH, NaHCO₃, KHCO₃, LiHCO₃, Na₂CO₃, K₂CO₃, Li₂CO₃,Mg(OH)₂, Ca(OH)₂, CaCO₃, MgCO₃, Ba(OH)₂, Be(OH)₂, BaCO₃, SrCO₃, and thelike or mixtures thereof.
 41. The process according to claim 33, furthercomprising crystallizing Vilazodone base from DMSO and water.
 42. Aprocess for preparation of a thermodynamically stable and substantiallypure amorphous form of Vilazodone hydrochloride, which comprises: a)providing a solution of Vilazodone hydrochloride in a first solvent or amixture of solvents; b) optionally, filtering said solvent solution toremove any extraneous matter; and c) substantially removing said solventfrom said solvent solution to afford amorphous form of Vilazodonehydrochloride.
 43. The process for preparation of a thermodynamicallystable and substantially pure amorphous form of Vilazodonehydrochloride, according to claim 42, wherein said Vilazodonehydrochloride preparation comprising: a) providing a solution ofVilazodone free base in said first solvent or a mixture of solventscapable of dissolving Vilazodone; and b) mixing with the solution ofhydrochloric acid dissolved in the second solvent.
 44. The process forpreparation of a thermodynamically stable and substantially pureamorphous form of Vilazodone hydrochloride of claim 42, wherein saidVilazodone hydrochloride is prepared in accordance with claim claim 33.45. The process according to claim 42, wherein said first solvent instep (a) is selected from the group consisting of formic acid, aceticacid, and propionic acid.
 46. The process according to claim 43, whereinsaid second solvent in step (b) is selected from the group consisting ofwater, alcohols, ketones, chlorinated hydrocarbons, hydrocarbons,nitriles, esters, cyclic ethers, aliphatic ethers, polar aproticsolvents, and mixtures thereof.
 47. The process according to claim 42,which comprises: a) providing a solution of Vilazodone hydrochloride informic acid; b) optionally, filtering the solvent solution to remove anyextraneous matter; and c) substantially removing the solvent from thesolution to afford amorphous form of Vilazodone hydrochloride.
 48. Theprocess according to claim 42, which comprises: a) providing a solutionof Vilazodone free base in formic acid; b) mixing with the solution ofaqueous HCl; c) optionally, filtering the solvent solution to remove anyextraneous matter; and d) substantially removing the solvent from thesolution to afford amorphous form of Vilazodone hydrochloride.
 49. Theprocess as claimed in claim 42, wherein said pure amorphous Vilazodonehydrochloride has a purity of greater than about 98%,
 50. The process asclaimed in claim 42, wherein said pure amorphous Vilazodonehydrochloride has a purity of greater than about 99.5%.
 51. The processas claimed in claim 42, wherein said pure amorphous Vilazodonehydrochloride is substantially free of the crystalline forms ofVilazodone.
 52. A process for the preparation of Vilazodone or a saltthereof and its amorphous form, comprising: a. reacting 5-nitrosalicaldehyde of formula (III) with 2-bromo diethyl malonate of formula(IV) to get compound of formula (V);

b. reducing compound of formula (V) to get compound of formula (VI);

c. converting compound of formula (VI) to compound of formula (VII);

d. Condensing compound of formula (VII) or salt thereof with compound offormula (VIII) to get compound of formula (II) or salt thereof;

e. reacting compound of formula (II) with source of ammonia to getcompound of formula (I); and

f. converting Vilazodone base of formula (I) into amorphous form ofVilazodone hydrochloride.